Triaromatic vitamin D analogues

ABSTRACT

The invention relates, as novel and useful industrial products, to triaromatic compounds, which are vitamin D analogues, of general formula (I):  
                 
 
     and also to a method for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.

CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119 ofFR-01/15924, filed Dec. 10, 2001, and of provisional application Ser.No. 60/351,433, filed Jan. 28, 2002, both hereby expressly incorporatedby reference. This application is also a continuation of said '433provisional.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field of the Invention

[0003] The invention relates, as novel and useful industrial products,to triaromatic compounds which are vitamin D analogues.

[0004] The invention also relates to a process for preparing them and totheir use in pharmaceutical compositions intended for use in human orveterinary medicine, or alternatively in cosmetic compositions.

[0005] The compounds according to the invention have pronounced activityin the fields of cell proliferation and differentiation and findapplications more particularly in the topical and systemic treatment ofdermatological (or other) complaints associated with a keratinizationdisorder, complaints with an inflammatory and/or immunoallergiccomponent and hyperproliferation of tissues of ectodermal origin (skin,epithelium, etc.), whether benign or malignant. These compounds can alsobe used to combat aging of the skin, whether photo-induced orchronological, and to treat cicatrization disorders.

[0006] The compounds according to the invention can also be used incosmetic compositions for body and hair hygiene.

[0007] 2. Description of the Prior Art

[0008] Vitamin D is an essential vitamin for preventing and treatingmineralization defects of cartilage (rickets) and of bone(osteomalacia), and even of certain forms of osteoporosis in elderlypeople. However, it is now accepted that its functions extend wellbeyond regulating bone metabolism and calcium homeostasis. Among thesefunctions, mention may be made of its actions on cell proliferation anddifferentiation and the control of the immune defenses. Their discoveryhas opened the way to novel therapeutic approaches in dermatology,carcinology and in the field of autoimmune diseases and that of organ ortissue transplants.

[0009] An efficient therapeutic supply has long been confounded by thetoxicity of this vitamin (occasionally fatal hypercalcaemia). Structuralanalogues of vitamin D are currently synthesized, some of which conserveonly the differentiating properties and have no action on calciummetabolism.

[0010] The Applicant has already proposed, in patent application WO01/38303, novel compounds that are vitamin D analogues, which showselective activity on cell proliferation and differentiation withouthaving a hypercalcaemiant nature.

SUMMARY OF THE INVENTION

[0011] The Applicant has just discovered, surprisingly, that certaincompounds not specifically described in patent application WO 01/38303show biological activity very much superior to that of the compoundsspecifically described. This activity is so strong that it is greaterthan or equal to the activity of 1,25-dihydroxyvitamin D₃.

[0012] Thus, the present invention relates to compounds of generalformula (I) below:

[0013] in which:

[0014] —X—Y represents a bond chosen from the following structures:

—CH₂—CH₂—

—CH₂—O—

—O—CH₂—

—CH₂—N(R₄)—

[0015] R₄ having the meanings given below,

[0016] R₁ represents a methyl radical or an ethyl radical,

[0017] R₂ represents an ethyl radical, a propyl radical or an isopropylradical,

[0018] R₃ represents an ethyl radical or a trifluoromethyl radical,

[0019] R₄ represents a hydrogen atom, a methyl radical, an ethyl radicalor a propyl radical,

[0020] and also to the optical and geometrical isomers thereof, and thesalts thereof.

[0021] The present invention also relates to the compounds describedabove when they are in the form of salts of a mineral or organic acid,in particular hydrochloric acid, sulfuric acid, acetic acid, fumaricacid, hemisuccinic acid, maleic acid and mandelic acid.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0022] Among the compounds of formula (I) falling within the context ofthe present invention, mention may be made especially of the following:

[0023] {5-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;

[0024]{5-[6,2′-Diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol;

[0025]{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;

[0026]{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;

[0027] (4-{2-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol;

[0028] {4-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-ylmethoxy]-2-hydroxymethylphenyl}methanol;

[0029](4-{[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;

[0030][4-({[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;

[0031][4-({Ethyl-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;

[0032][4-({[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]propylamino}methyl)-2-hydroxymethylphenyl]methanol;

[0033](2-Hydroxymethyl-4-{2-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]ethyl}phenyl)methanol;

[0034]{2-Hydroxymethyl-4-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yloxymethyl]phenyl}methanol;

[0035]{2-Hydroxymethyl-4-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylmethoxy]phenyl}methanol;

[0036](2-Hydroxymethyl-4-{[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylamino]methyl}phenyl)methanol;

[0037][2-Hydroxymethyl-4-({N-methyl[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)phenyl]methanol;

[0038][4-({N-Ethyl[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;

[0039][2-Hydroxymethyl-4-({[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]N-propyl-amino}methyl)phenyl]methanol;

[0040](4-{2-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxy-methylphenyl)methanol;

[0041]{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ylmethoxy]-2-hydroxy-methylphenyl}methanol;

[0042](4-{[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;

[0043][4-({[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;

[0044][4-({Ethyl-[6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;

[0045][4-({[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]propylamino}methyl)-2-hydroxymethylphenyl]methanol;

[0046](4-{2-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol;

[0047]{4-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;

[0048]{4-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylmethoxy]-2-hydroxymethylphenyl}methanol;

[0049](4-{[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;

[0050][4-({[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;

[0051][4-({N-Ethyl[6-ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;

[0052][4-({[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]-N-propyl-amino}methyl)-2-hydroxymethylphenyl]methanol;

[0053](4-{[4′-(1-Ethyl-1-hydroxypropyl)-6,2′-dimethylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol.

[0054] According to the present invention, the compounds of formula (I)that are more particularly preferred are those for which at least one,and preferably all, of the conditions below are satisfied:

[0055] (i) —X—Y represents —CH₂—CH₂—;

[0056] (ii) R₁ is an ethyl radical;

[0057] (iii) R₂ is a propyl radical;

[0058] (iv) R₃ is an ethyl radical.

[0059] A Subject of the present invention is also processes forpreparing the compounds of formula (I) according to the reaction schemespresented in FIG. 1.

[0060] When —X—Y— represents a bond of structure —CH₂—O— or —CH₂—N(R₄)—,the compounds of formula (Ia) are preferably prepared from compounds (1)and (2), obtained according to the reaction schemes of FIG. 2.

[0061] The compounds (1) (when Y═O) and (2) may be obtained,respectively, from compounds (4) and (9), firstly by forming thetrifluoromethanesulfonate derivatives ((5) and (10), respectively) inthe presence of trifluoromethanesulfonic anhydride and a base such astriethylamine in dichloromethane. Next, by means of a Suzuki couplingreaction with the boronic acid derivatives (6) in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium (0), thederivatives (7) and (11) are respectively obtained, followed by acoupling reaction with the bromo derivatives (8) in the presence ofpotassium carbonate in methyl ethyl ketone. When Y═NR₄, compound (1) maybe obtained from compound (12), firstly by a Suzuki coupling reactionwith the boronic acid derivative (13) in the presence of a catalyst suchas tetrakis(triphenylphosphine)palladium (0), to give the derivative(14), followed by a coupling reaction with the bromo derivatives (8) inthe presence of sodium hydride in dimethylformamide.

[0062] When —X—Y— represents a bond of structure —CH₂—CH₂—, thecompounds of formula (Ia) shown in FIG. 1 are prepared from thecompounds (3), obtained according to the reaction scheme shown in FIG.3.

[0063] Via a Suzuki reaction of the trifluoromethanesulfonatederivatives (5) with the boronic acid derivatives (15) in the presenceof a catalyst such as tetrakis(triphenylphosphine)palladium(0) and abase such as potassium carbonate in a solvent such as1,2-dimethoxyethane, the compounds (16) are obtained. These compoundsare converted into the compounds (18) by a Horner-Emmons reaction withcompound (17), and then into the compounds (19) by protecting the ketonefunction in dioxolane form (ethylne glycol, para-toluenesulfonic acid,toluene). Reduction of the double bond in the presence ofpalladium-on-charcoal in a solvent such as methanol gives the compounds(3).

[0064] Compound (6) may be obtained according to the reaction scheme ofFIG. 4. Compounds (8) and (17) may be obtained according to the reactionscheme of FIG. 5. Compounds (12) and (13) may be obtained according tothe reaction scheme of FIG. 6. Compound (15) may be obtained accordingto the reaction scheme of FIG. 7.

[0065] When R₃ represents a trifluoromethyl radical, the compounds (I)may be obtained from the corresponding bromo derivative by formation ofthe organomagnesium or organolithium derivative followed by reactionwith hexafluoroacetone.

[0066] The compounds according to the invention show biologicalproperties analogous to those of vitamin D, especially properties oftransactivation of the vitamin D response elements (VDRE), such asagonist or antagonist activity with respect to receptors of vitamin D orits derivatives. The expression “D vitamins or derivatives thereof”means, for example, the derivatives of vitamin D₂ or D₃ and inparticular 1,25-dihydroxyvitamin D₃ (calcitriol).

[0067] This agonist activity with respect to receptors of vitamin D orof derivatives thereof may be demonstrated “in vitro” by methods knownin the field of study of gene transcription (Hansen et al., The SocietyFor Investigative Dermatology, vol.1, No. 1, April 1996).

[0068] The biological properties analogous to vitamin D may also bemeasured by means of the capacity of the product to induce thedifferentiation of promyelocytic leukemia cells HL60. The protocol andalso the results obtained with the compounds according to the inventionare described in Example 8 of the present patent application.

[0069] By way of example, the VDR agonist activity may be tested on theHeLa cell line by cotransfection of an expression vector of the humanVDR receptor and of the reporter plasmid p240Hase-CAT. The agonistactivity may also be characterized in this cotransfection system, bydetermining the dose required to achieve 50% of the maximum activity ofthe product (AC50). The details of the protocol for this test and theresults obtained with the compounds according to the invention aredescribed in Example 9 of the present patent application.

[0070] The biological properties analogous to vitamin D may also bemeasured by means of the capacity of the product to inhibit theproliferation of normal human keratinocytes (NHK in culture). Theproduct is added to NHKs cultured under conditions promoting theproliferative state. The product is left in contact with the cells forfive days. The number of proliferative cells is measured byincorporation of bromodeoxyuridine (BRdU) into the DNA. The protocol forthis test and the results obtained with the compounds according to theinvention are described in Example 10 of the present patent application.

[0071] A subject of the present invention is also, as a medicinalproduct, the compounds described above. The compounds according to theinvention are particularly suitable in the following fields oftreatment:

[0072] 1) for treating dermatological complaints associated with adifferentiation or proliferation disorder of keratinocytes or sebocytes,especially for treating common acne, comedones, polymorphonuclearleukocytes, acne rosacea, nodulocystic acne, acne conglobata, senileacne and secondary acnes such as solar acne, acne medicamentosa oroccupational acne;

[0073] 2) for treating keratinization disorders, especially ichthyosis,ichthyosiform conditions, Darier's disease, palmoplantar keratoderma,leukoplakia and leukoplakiform conditions, and cutaneous or mucous(buccal) lichen;

[0074] 3) for treating other dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent, and especially all forms of psoriasis, whether cutaneous,mucous or ungual psoriasis, and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema or respiratory atopy, oralternatively gingival hypertrophy;

[0075] 4) for treating certain inflammatory complaints not showing akeratinization disorder, such as atopic eczema and contact allergies;

[0076] 5) for treating all dermal or epidermal proliferations, whetherbenign or malignant, and whether of viral origin or not, such as commonwarts, flat warts and verruciform epidermodysplasia, oral or floridpapillomatoses and proliferations that may be induced by ultravioletradiation, especially in the case of basocellular and spinocellularepithelioma;

[0077] 6) for treating other dermatological disorders such as bullousdermatosis and collagen diseases;

[0078] 7) for preventing or treating the signs of aging of the skin,whether photo-induced or chronological aging, or for reducing actinickeratosis and pigmentations, or any cutaneous pathologies associatedwith chronological or actinic aging;

[0079] 8) for preventing or treating cicatrization disorders or forpreventing or repairing stretch marks;

[0080] 9) for controlling sebaceous function disorders such as acneichyperseborrhoea or simple seborrhoea or alternatively seborrhoeiceczema;

[0081] 10) for treating certain ophthalmological disorders, especiallycorneopathies;

[0082] 11) in the treatment or prevention of cancerous or precancerousconditions of cancers presenting or being able to be induced to presentvitamin D receptors, such as, but without limitation, breast cancer,leukaemia, myelodysplasic syndromes and lymphomas, carcinomas of thecells of the malpighian epithelium and gastrointestinal cancers,melanomas and osteosarcoma;

[0083] 12) in the treatment of inflammatory complaints such as arthritisor rheumatoid arthritis;

[0084] 13) in the treatment of any cutaneous or general complaint ofviral origin;

[0085] 14) in the prevention or treatment of alopecia of variousorigins, especially chemotherapy-induced or radiation-induced alopecia;

[0086] 15) in the treatment of dermatological or general complaints withan immunological component;

[0087] 16) in the treatment of immune complaints, such as autoimmunediseases (for instance, but without limitation, type 1 sugar diabetes,multiple sclerosis, lupus and lupus-type complaints, asthma,glomerulonephritis, etc.), selective dysfunctions of the immune system(for example AIDS) and the prevention of immune rejection [for instancegraft rejections (for example kidney, heart, bone marrow, liver,pancreatic islets or the whole pancreas, the skin, etc.) or theprevention of graft-versus-host disease];

[0088] 17) in the treatment of endocrine complaints, given that thevitamin D analogues can modulate hormonal secretion, such as increasingthe secretion of insulin or selectively suppressing the secretion ofparathyroid hormone (for example in chronic renal insufficiency andsecondary hyperparathyroidism);

[0089] 18) in the treatment of complaints characterized by abnormalmanagement of intracellular calcium; and

[0090] 19) in the treatment and/or prevention of vitamin D deficienciesand other complaints of homeostasis of minerals in the plasma and thebones, such as rickets, osteomalacia, osteoporosis, especially in thecase of menopausal women, renal osteodystrophy and parathyroid functiondisorders.

[0091] A subject of the present invention is also a pharmaceuticalcomposition comprising at least one compound as defined above in apharmaceutically acceptable support.

[0092] The compounds according to the invention may be administeredenterally, parenterally, topically or ocularly.

[0093] Via the enteral route, the pharmaceutical compositions may be inthe form of tablets, gel capsules, sugar-coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, or suspensions ofpolymeric or lipid vesicles or nanospheres or microspheres allowingcontrolled release.

[0094] Via the parenteral route, the compositions may be in the form ofsolutions or suspensions for infusion or for injection.

[0095] The compounds according to the invention are generallyadministered at a daily dose of about from 0.001 μg/kg to 1000 μg/kg andpreferably of about from 0.01 μg/kg to 100 μg/kg of body weight in 1 to3 dosage intakes.

[0096] Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are intended for treating the skin,the scalp and mucous membranes and are in the form of ointments, creams,milks, pomades, powders, impregnated pads, solutions, gels, sprays,lotions or suspensions. They may also be in the form of suspensions ofpolymeric or lipid vesicles or nanospheres or microspheres or polymericpatches and hydrogels allowing controlled release. These topical-routecompositions may be either in anhydrous form or in aqueous formdepending on the clinical indication.

[0097] Via the ocular route, they are mainly eye lotions.

[0098] These compositions for the topical or ocular route contain atleast one compound according to the invention in a concentrationpreferably of between 0.0001% and 5% and preferably between 0.001% and1% relative to the total weight of the composition.

[0099] The compounds according to the invention also find an applicationin cosmetics, in particular in body and hair hygiene and especially fortreating acne-prone skin, for regrowth of the hair, or for preventinghair loss, for controlling the greasy appearance of the skin or thehair, in protecting against the harmful effects of sunlight or in thetreatment of dry skin, and for preventing and/or treating photo-inducedor chronological aging of the skin.

[0100] The present invention is thus also directed towards a cosmeticcomposition containing, in a cosmetically acceptable support, at leastone compound as defined above.

[0101] This cosmetic composition may especially be in the form of acream, a milk, a lotion, a gel, a suspension of polymeric or lipidvesicles or nanospheres or microspheres, a soap or a shampoo.

[0102] The concentration of compound of general formula (I) in thecosmetic composition according to the invention may be between 0.001%and 3% by weight relative to the total weight of the composition.

[0103] In the pharmaceutical and cosmetics fields, the compoundsaccording to the invention may advantageously be used in combinationwith inert additives or even pharmacodynamically or cosmetically activeadditives or combinations of these additives, and especially:

[0104] wetting agents;

[0105] flavor enhancers;

[0106] preserving agents such as para-hydroxybenzoic acid esters;

[0107] stabilizers;

[0108] moisture regulators;

[0109] pH regulators;

[0110] osmotic pressure modifiers;

[0111] emulsifiers;

[0112] UV-A and UV-B screening agents;

[0113] antioxidants such as α-tocopherol, butylhydroxyanisole,butylhydroxytoluene, superoxide dismutase, ubiquinol or certainmetal-chelating agents;

[0114] depigmenting agents such as hydroquinone, azelaic acid, caffeicacid or kojic acid;

[0115] emollients;

[0116] moisturizers, for instance glycerol, PEG 400, thiamorpholinoneand its derivatives or urea;

[0117] antiseborrhoeic or antiacne agents, such asS-carboxymethylcysteine, S-benzyl-cysteamine, salts thereof andderivatives thereof, or benzoyl peroxide;

[0118] antibiotics, for instance erythromycin and its esters, neomycin,clindamycin and its esters, and tetracyclines;

[0119] antifungal agents such as ketoconazole orpoly-4,5-methylne-3-isothiazolinones;

[0120] agents for promoting regrowth of the hair, for instance Minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives,Diazoxide (7-chloro 3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) andPhenytoin (5,4-diphenylimidazolidine-2,4-dione);

[0121] non-steroidal anti-inflammatory agents;

[0122] carotenoids and especially β-carotene;

[0123] anti-psoriatic agents such as anthralin and its derivatives;

[0124] eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid,and esters and amides thereof;

[0125] retinoids, i.e., natural or synthetic RAR or RXR receptorligands;

[0126] corticosteroids or oestrogens;

[0127] α-hydroxy acids and α-keto acids or derivatives thereof, such aslactic acid, malic acid, citric acid, glycolic acid, mandelic acid,tartaric acid, glyceric acid or ascorbic acid, and also salts, amides oresters thereof, or β-hydroxy acids or derivatives thereof, such assalicylic acid and its salts, amides or esters;

[0128] ion-channel blockers such as potassium-channel blockers;

[0129] or alternatively, more particularly for pharmaceuticalcompositions, in combination with medicinal products known to interferewith the immune system (for example cyclosporin, FK 506,glucocorticoids, monoclonal antibodies, cytokines or growth factors,etc.).

[0130] Needless to say, a person skilled in the art will take care toselect the optional compound(s) to be added to these compositions suchthat the advantageous properties of the compounds of the presentinvention are not, or are not substantially, adversely affected by theenvisaged addition.

[0131] Examples of the production of the active compounds of generalformula (I) according to the invention, and also various concreteformulations based on such compounds and tests to evaluate thebiological activity of the compounds according to the invention, willnow be given, for illustrative purposes and with no limiting nature.

EXAMPLE 1

[0132]{5-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxy-methyl]-2-hydroxymethylphenyl}methanol.

[0133] (a) 1-(4-Hydroxy-3-propylphenyl)propan-1-one

[0134] 7.1 g (53 mmol) of aluminum chloride are placed in 70 ml ofnitrobenzene in a round-bottomed flask and under a stream of nitrogen.The mixture is heated at 70° C. until dilution is complete. It is thencooled to 0° C. and 7.2 ml (52 mmol) of 2-propylphenol are added. Themixture is allowed to warm to room temperature and is then heated to 40°C. 4.6 ml (52 mmol) of propionyl chloride are then added dropwise. Thereaction medium is heated at 40° C. for 2 hours and then stirred for 48hours at room temperature. It is then poured into ice with 20 ml ofconcentrated hydrochloric acid. After extraction with ethyl ether, theorganic phase is washed with 2N sodium hydroxide. The aqueous phases areacidified with hydrochloric acid and extracted with ether. The organicphase is dried over magnesium sulfate, filtered and then evaporated. Theblack solid obtained is triturated in heptane, filtered off and dried.3.5 g (35%) of the expected product are obtained in the form of a blackpowder.

[0135] (b) 4-Propionyl-2-propylphenyl 1,1,1-trifluoromethanesulfonate

[0136] 3.4 g (18 mmol) of 1-(4-hydroxy-3-propylphenyl)-1-propanone areplaced in 100 ml of dichloromethane in a round-bottomed flask and undera stream of nitrogen. The reaction medium is cooled to 0° C. and 3.3 ml(23 mmol) of triethylamine are then added. 15 minutes later, 4.3 ml (26mmol) of trifluoromethanesulfonic anhydride are added. 1 hour later, themixture is poured into saturated aqueous ammonium chloride solution andextracted with dichloromethane. The organic phase is dried overmagnesium sulfate, filtered and then evaporated. The residue obtained ispurified by chromatography on a column of silica eluted with a mixtureof heptane and ethyl acetate (70/30). After evaporating off thesolvents, 5.4 g (93%) of the expected product are obtained in the formof a brown oil.

[0137] (c) 3-Bromo-4-methylphenylamine

[0138] 30 g (139 mmol) of 2-bromo-4-nitrotoluene are placed in 180 ml ofwater, 400 ml of ethanol and 110 ml of acetic acid in a round-bottomedflask and under a stream of nitrogen. The medium is heated to 70° C. and31 g (556 mmol) of iron are added portionwise. The mixture is refluxedfor 2 hours and, after cooling, 180 ml of 34% aqueous ammonia are addedslowly. The mixture is filtered through Celite and the organic phase isextracted with water and ethyl acetate. It is then dried over magnesiumsulfate, filtered and then evaporated. 25.5 g (100%) of the expectedproduct are obtained in the form of a brown oil.

[0139] (d) 3-Bromo-4-methylphenol

[0140] 25 g (134 mmol) of 2-bromo-4-aminotoluene are placed in 400 ml of1M sulfuric acid in a round-bottomed flask, and the mixture is thencooled to 0° C. 13 g (190 mmol) of sodium nitrite dissolved in 30 ml ofwater are added, followed by addition of 21 ml of concentrated sulfuricacid. The mixture is refluxed for 4 hours. It is then extracted withethyl ether. The organic phase is dried over magnesium sulfate, filteredand then evaporated. The residue obtained is purified by chromatographyon a column of silica eluted with a mixture of heptane and ethyl acetate(90/10) to give 12.1 g (48%) of the expected product in the form of abrown oil.

[0141] (e) 2-Bromo-4-ethoxymethoxy-1-methylbenzene

[0142] 12.1 g (65 mmol) of 3-bromo-4-methylphenol are placed in 100 mlof dry dimethylformamide in a round-bottomed flask and under a stream ofnitrogen. At 0° C., 3.1 g (78 mmol) of 60% sodium hydride are addedslowly. After 1 hour, 7.3 ml (78 mmol) of methoxyethyl chloride areadded dropwise. The mixture is stirred at room temperature overnight. Itis then poured into water and extracted with ethyl acetate. The organicphase is dried over magnesium sulfate, filtered and then evaporated. Theresidue obtained is purified by chromatography on a column of silicaeluted with a mixture of heptane and ethyl acetate (85/15) to give 13.2g (83%) of the expected product in the form of an oil.

[0143] (f) 5-Ethoxymethoxy-2-methylphenylboronic acid

[0144] 1.4 g (59 mmol) of magnesium turnings are placed intetrahydrofuran in a round-bottomed flask and under a stream ofnitrogen. 13.2 g (54 mmol) of 2-bromo-4-ethoxymethoxy-1-methylbenzenediluted in a small amount of THF are added slowly. The medium isrefluxed for 20 minutes. It is then added via a cannula to 15 ml (65mmol) of triisopropyl borate. The mixture sets to a solid and is thenpoured into 1N hydrochloric acid solution and extracted with ether. Theorganic phase is dried over magnesium sulfate, filtered and thenevaporated. 9.8 g (87%) of the expected product are obtained in the formof a brown oil.

[0145] (g)1-(5′-Ethoxymethoxy-2′methyl-2-propylbiphenyl-4-yl)propan-1-one

[0146] 1.56 g (7.4 mmol) of 5-ethoxymethoxy-2-methylphenylboronic acid,2 g (6.2 mmol) of 4-propionyl-2-propylphenyl1,1,1-trifluoromethanesulfonate, 517 mg (12 mmol) of lithium chlorideand 7.4 ml of 2M potassium carbonate solution are dissolved in 50 ml of1,2-dimethoxyethane in a round-bottomed flask and under a stream ofnitrogen. The mixture is refluxed for 10 hours. It is then poured intowater and extracted with ethyl acetate. The organic phase is dried overmagnesium sulfate, filtered and then evaporated. A brown oil isobtained, which is used without further purification for the rest of thesynthesis.

[0147] (h) 1-(5′-Hydroxy-2′-methyl-2-propylbiphenyl-4-yl)propan-1-one.CS 755.064

[0148] 1-(5′-Ethoxymethoxy-2′-methyl-2-propylbiphenyl-4-yl)propan-1-one,obtained in step (g), is dissolved in methanol and a few drops ofsulfuric acid are added. Stirring is continued overnight and the mediumis then extracted with ethyl acetate and water. The organic phase isdried over magnesium sulfate, filtered and then evaporated. The residueobtained is purified by chromatography on a column of silica eluted witha mixture of heptane and ethyl acetate (75/25) to give 1.53 g (88%) ofthe expected product in the form of a brown oil.

[0149] (i) Dimethyl 4-hydroxymethylphthalate

[0150] 50 g (260 mmol) of trimellitic anhydride are placed in 500 ml ofdioxane in a round-bottomed flask and under a stream of nitrogen. 520 ml(520 mmol) of borane (1M/THF) are added dropwise and the mixture isstirred for 48 hours at room temperature. The reaction medium is thenpoured slowly into saturated aqueous ammonium chloride solution andextracted with dichloromethane. The organic phase is dried overmagnesium sulfate, filtered and then evaporated. The residue isdissolved in 400 ml of methanol and 5 ml of sulfuric acid are added. Theresulting mixture is heated at 80° C. overnight. The methanol isevaporated off and the residue is taken up in ethyl acetate and washedwith water. The organic phase is dried over magnesium sulfate, filteredand then evaporated. 52.7 g (90%) of the expected product are obtainedin the form of a yellow oil.

[0151] (j) Dimethyl 4-(tert-butyldimethylsilanyloxymethyl)phthalate

[0152] 19 g (84.8 mmol) of dimethyl 4-hydroxymethylphthalate are placedin 250 ml of dimethylformamide in a round-bottomed flask and under astream of nitrogen. 14 g (93 mmol) of tert-butyldimethylsilyl chlorideand 8 g (118 mmol) of imidazole are added. The reaction medium isstirred for 3 hours at room temperature, it is then concentrated and theresidue is dissolved in ether and then filtered. The filtrate isevaporated and the product is purified by chromatography on a column ofsilica eluted with a mixture of heptane and ethyl acetate (50/50) togive 23.7 g (83%) of the expected product in the form of a yellow oil.

[0153] (k)[4-(tert-Butyldimethylsilanyloxymethyl)-2-hydroxymethylphenyl]methanol

[0154] 17.8 g (469 mmol) of lithium aluminum hydride are placed in 800ml of ethyl ether in a round-bottomed flask and under a stream ofnitrogen. At 0° C., a solution of 66.4 g (196 mmol) of dimethyl4-(tert-butyldimethylsilanyloxymethyl)phthalate in 200 ml of ether and100 ml of THF is added dropwise. The reaction medium is stirred at 0° C.for 2 hours. 18 ml of water, 18 ml of 15% sodium hydroxide solution andthen 54 ml of water are added very slowly. The precipitate formed isfiltered off and rinsed with ether, and the filtrate is evaporated. 52 g(94%) of the expected product are obtained in the form of a colorlessoil.

[0155] (l)2-Benzoyloxymethyl-4-(tert-butyldimethylsianyloxymethyl)benzyl benzoate

[0156] 40 g (141 mmol) of[4-(tert-butyldimethylsilanyloxymethyl)-2-hydroxymethylphenyl]-methanolare placed in 400 ml of THF in a round-bottomed flask and under a streamof nitrogen. At 0° C., 49 ml (352 mmol) of triethylamine are added,followed by dropwise addition of 34.5 ml (297 mmol) of benzoyl chloride.The reaction medium precipitates and 350 mg (2.8 mmol) ofdimethylaminopyridine are then added. The mixture is allowed to warm toroom temperature overnight. The medium is filtered and the solid iswashed with ethyl acetate. The filtrate is evaporated and the residue istaken up in dichloromethane. The organic phase is washed with saturatedaqueous ammonium chloride solution and then with water. It is then driedover magnesium sulfate, filtered and evaporated. 69.5 g (100%) of theexpected product are obtained in the form of an orange-colored oil.

[0157] (m) 2-Benzoyloxymethyl-4-hydroxymethylbenzyl benzoate

[0158] 69 g (140 mmol) of2-benzoyloxymethyl-4-(tert-butyldimethylsilanyloxymethyl)benzyl benzoateare placed in 450 ml of ethyl acetate in a round-bottomed flask andunder a stream of nitrogen. 178 ml of tetrabutylammonium fluoride(1M/THF) are added. The medium is stirred for 30 minutes at roomtemperature. It is then poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic phase is driedover magnesium sulfate, filtered and then evaporated. The residue ispurified by chromatography on a column of silica eluted with a mixtureof heptane and ethyl acetate (40/60) to give 46.6 g (88%) of theexpected product in the form of a white powder with a melting point of92° C.

[0159] (n) 3,4-bis(benzoyloxymethyl)benzyl bromide

[0160] 40 g (106 mmol) of 2-benzoyloxymethyl-4-hydroxymethylbenzylbenzoate are placed in 500 ml of dichloromethane and 77.6 g (234 mmol)of carbon tetrabromide in a round-bottomed flask and under a stream ofnitrogen. At 0° C., a solution of 61.3 g (233 mmol) oftriphenylphosphine in 200 ml of dichloromethane is added dropwise. Themixture is allowed to warm to room temperature over 2 hours. Thereaction medium is poured into water and extracted with dichloromethane.The organic phase is dried over magnesium sulfate, filtered and thenevaporated. The residue is purified by chromatography on a column ofsilica eluted with a mixture of heptane and ethyl acetate (70/30) togive 32.6 g (70%) of the expected product in the form of a white powder.

[0161] (o)1-{5′[3,4-Bis(benzoyloxymethyl)benzyloxy]-2′methyl-2-propylbiphenyl-4-yl}-1-propanone

[0162] 1.5 g (5.4 mmol) of1-(5′-hydroxy-2′-methyl-2-propylbiphenyl-4-yl)-1-propanone, 2.5 g (5.7mmol) of (3,4-bis(benzoyloxymethyl)benzyl bromide and 750 mg (5.4 mmol)of potassium carbonate are placed in 50 ml of methyl ethyl ketone in around-bottomed flask and under a stream of nitrogen. The mixture isrefluxed overnight and, after cooling, it is filtered through Celite.The filtrate is extracted with water and ethyl acetate. The organicphase is dried over magnesium sulfate, filtered and then evaporated. Theresidue obtained is purified by chromatography on a column of silicaeluted with a mixture of heptane and ethyl acetate (85/15) to give 1.93g (56%) of the expected product in the form of a dark yellow oil.

[0163] (p)1-{5′[3,4-Bis(hydroxymethyl)benzyoxyl]-2′methyl-2-propylbiphenyl-4-yl}-1-propanone

[0164] 1.9 g (3 mmol) of1-{5′-[3,4-bis(benzoyloxymethyl)benzyloxy]-2′-methyl-2-propylbiphenyl-4-yl}-1-propanoneare dissolved in 40 ml of methanolic 2% potassium carbonate solution ina round-bottomed flask. The mixture is stirred at room temperatureovernight. It is then poured into water and extracted with ethylacetate. The organic phase is dried over magnesium sulfate, filtered andthen evaporated. The residue obtained is purified by chromatography on acolumn of silica eluted with a mixture of heptane and ethyl acetate(70/30) to give 890 mg (69%) of the expected product.

[0165] (q){5-[4′(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0166] 890 mg (2 mmol) of1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-methyl-2-propylbiphenyl-4-yl}-1-propanoneare placed in 40 ml of dry THF in a round-bottomed flask and under astream of nitrogen. At 0° C., 4.1 ml (12 mmol) of ethylmagnesium bromideare added. The reaction medium is stirred at room temperature for 1 hour30 minutes and then poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic phase is driedover magnesium sulfate, filtered and then evaporated. The residueobtained is purified by chromatography on a column of silica eluted witha mixture of heptane and ethyl acetate (50/50) to give 550 mg (64%) of{5-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanolin the form of white crystals with a melting point of 97° C.

EXAMPLE 2

[0167]{5-[6,2′-Diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0168] (a) 4-Bromo-2-ethylphenol

[0169] 5.57 g (45 mmol) of 2-ethylphenol are placed in 250 ml ofchloroform in a round-bottomed flask and under a stream of nitrogen.43.4 g (90 mmol) of tetrabutylammonium tribromide are added portionwise.The medium is stirred for 1 hour at room temperature and is thenhydrolysed with saturated aqueous sodium thiosulfate solution. Theorganic phase is washed with water, dried over magnesium sulfate,filtered and then evaporated. 9.1 g (100%) of the expected product areobtained in the form of a yellow oil.

[0170] (b) (4-Bromo-2-ethylphenoxy)-tert-butyldimethylsilane

[0171] In a manner similar to that of Example 1(j), starting with 9.1 g(45 mmol) of 4-bromo-2-ethylphenol, and after purification bychromatography on a column of silica eluted with heptane, 11.9 g (83%)of the expected product are obtained in the form of a colorless oil.

[0172] (c) 1-[4-(tert-Butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-ol

[0173] 11.9 g (38 mmol) of(4-bromo-2-ethylphenoxy)-tert-butyldimethylsilane are placed in 200 mlof THF in a round-bottomed flask and under a stream of nitrogen. Thereaction medium is cooled to −78° C. and 16.6 ml (41 mmol) ofn-butyllithium (2.5 M/THF) are added dropwise. 30 minutes later, 3.2 ml(45 mmol) of propionaldehyde are added dropwise. The medium is stirredfor 3 hours at −78° C. It is then poured into saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic phase isdried over magnesium sulfate, filtered and then evaporated. 11.1 g(100%) of the expected product are obtained in the form of a colorlessoil.

[0174] (d)1-[4-(tert-Butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-one

[0175] 11.1 g (37 mmol) of1-[4-(tert-butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-ol are placedin 100 ml of dichloromethane in a round-bottomed flask, and 32.8 g (377mmol) of manganese dioxide are added. The medium is stirred overnight atroom temperature. It is then filtered through Celite and rinsed withdichloromethane. The filtrate is evaporated and the residue is purifiedby chromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (90/10) to give 6.8 g (62%) of the expected product inthe form of an orange-colored oil.

[0176] (e) 1-(3-Ethyl-4-hydroxyphenyl)propan-1-one

[0177] In a manner similar to that of Example 1(m), starting with 6.8 g(23 mmol) of1-[4-(tert-butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-one in 50 mlof THF, 4.1 g (100%) of the expected product are obtained in the form ofa beige-colored oil.

[0178] (f) 2-Ethyl-4-propionylphenyl 1,1,1-trifluoromethanesulfonate

[0179] In a manner similar to that of Example 1(b), by reacting 4.6 g(26.3 mmol) of 1-(3-ethyl-4-hydroxyphenyl)propan-1-one with 4.8 ml (28.9mmol) of trifluoromethanesulfonic anhydride, 8.1 g (99%) of the expectedproduct are obtained in the form of a brown oil.

[0180] (g) 1-Bromo-2-ethyl-5-nitrobenzene

[0181] 25 g (165 mmol) of 4-ethylnitrobenzene are placed in 200 ml ofdichloromethane in a round-bottomed flask and under a stream ofnitrogen. 20 ml (230 mmol) of trifluoromethanesulfonic acid and 33 g(115 mmol) of 1,3-dibromo-5,5-dimethylhydantoin are added and thereaction medium is stirred for 2 hours at room temperature. Saturatedaqueous sodium hydrosulfite solution is then added. The phases areseparated and the organic phase is neutralized with aqueous 2M sodiumcarbonate solution and then washed with water. It is then dried overmagnesium sulfate, filtered and evaporated. 35 g (92%) of the expectedproduct are obtained in the form of a yellow oil.

[0182] (h) 3-Bromo-4-ethylphenylamine

[0183] In a manner similar to that of Example 1(c), by reacting 34 g(148 mmol) of 1-bromo-2-ethyl-5-nitrobenzene with 33 g (591 mmol) ofiron, and after purification by chromatography on a column of silicaeluted with a mixture of heptane and ethyl acetate (90/10), 27 g (89%)of the expected product are obtained in the form of a yellow oil.

[0184] (i) 3-Bromo-4-ethylphenol

[0185] In a manner similar to that of Example 1(d), by reacting 27 g(135 mmol) of 3-bromo-4-ethylphenylamine with 11 g (162 mmol) of sodiumnitrite, and after purification by chromatography on a column of silicaeluted with a mixture of heptane and ethyl acetate (90/10), 13 g (49%)of the expected product are obtained in the form of a brown oil.

[0186] (j) 1-Bromo-2-ethyl-5-ethoxymethoxybenzene

[0187] In a manner similar to that of Example 1(e), by reacting 13 g (65mmol) of 3-bromo-4-ethylphenol with 6.7 ml (72 mmol) of methoxyethylchloride, and after purification by chromatography on a column of silicaeluted with a mixture of heptane and ethyl acetate (90/10), 12 g (76%)of the expected product are obtained in the form of a yellow oil.

[0188] (k) 2-Ethyl-5-ethoxymethoxyphenylboronic acid

[0189] 12 g (49 mmol) of 1-bromo-2-ethyl-5-ethoxymethoxybenzene areplaced in 200 ml of dry THF in a round-bottomed flask and under a streamof nitrogen. The reaction medium is cooled to −78° C. and 23 ml (58mmol) of 2.5M n-butyllithium in hexane are added dropwise. 20 minuteslater, 13.6 ml (59 mmol) of triisopropyl borate are added slowly.Stirring is continued for 1 hour at −78° C. The mixture is then pouredinto a solution of water and hydrochloric acid and is then extractedwith ethyl acetate. The organic phase is dried over magnesium sulfate,filtered and evaporated. The residue obtained is purified bychromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (50/50). After evaporating off the solvents, 6.7 g(65%) of the expected product are obtained in the form of whitecrystals.

[0190] (l) 1-(5′-Ethoxymethoxy-2,2′-diethylbiphenyl-4-yl)propan-1-one

[0191] In a manner similar to that of Example 1(g), by reacting 2 g (8.9mmol) of 2-ethyl-5-ethoxymethoxyphenylboronic acid with 2.1 g (6.9 mmol)of 2-ethyl-4-propionylphenyl 1,1,1-trifluoromethanesulfonate, a blackoil is obtained, which is used without further purification for the restof the synthesis.

[0192] (m) 1-(2,2′-Diethyl-5′-hydroxybiphenyl-4-yl)propan-1-one

[0193] In a manner similar to that of Example 1(h), starting with1-(5′-ethoxymethoxy-2,2′-diethylbiphenyl-4-yl)propan-1-one, and afterpurification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (50/50), 1.6 g (86%) of theexpected product are obtained in the form of a yellow oil.

[0194] (n)1-{5′-[3,4-Bis(benzoyloxymethyl)benzyloxy]-2,2′-diethylbiphenyl-4-yl}-1-propanone

[0195] In a manner similar to that of Example 1(o), by reacting 1.67 g(5.9 mmol) of 1-(2,2′-diethyl-5′-hydroxybiphenyl-4-yl)-1-propanone with2.73 g (6.2 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, and afterpurification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (95/5), 1.88 g (50%) of theexpected product are obtained in the form of an oil.

[0196] (o)1-{5′-[3,4-Bis(hydroxymethyl)benzyloxy]-2,2′-diethylbiphenyl-4-yl}-1-propanone

[0197] In a manner similar to that of Example 1(p), starting with 1.8 g(2.9 mmol) of1-{5′-[3,4-bis(benzoyloxymethyl)benzyloxy]-2,2′-diethylbiphenyl-4-yl}-1-propanone,and after purification by chromatography on a column of silica elutedwith a mixture of heptane and ethyl acetate (40/60), 840 mg (68%) of theexpected product are obtained in the form of a colorless oil.

[0198] (p){5-[6,2′-Diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol

[0199] In a manner similar to that of Example 1(q), by reacting 840 mg(1.9 mmol) of1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2,2′-diethylbiphenyl-4-yl}-1-propanonewith 5.2 ml (16 mmol) of ethylmagnesium bromide (3M/ether), and afterpurification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (40/60), 254 mg (29%) of{5-[6,2′-diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanolare obtained in the form of white crystals with a melting point of 93°C.

EXAMPLE 3

[0200]{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0201] (a)1-(5′-Ethoxymethoxy-2′-ethyl-2-propylbiphenyl-4-yl)propan-1-one

[0202] In a manner similar to that of Example 1(g), by reacting 1.58 g(7.1 mmol) of 2-ethyl-5-ethoxymethoxyphenylboronic acid obtained in 2(j)with 1.76 g (5.4 mmol) of 4-propionyl-2-propylphenyl1,1,1-trifluoromethanesulfonate obtained in 1(b), a brown oil isobtained, which is used without purification.

[0203] (b) 1-(2′-Ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)propan-1-one

[0204] In a manner similar to that of Example 1(h), starting with1-(5′-ethoxymethoxy-2′-ethyl-2-propylbiphenyl-4-yl)-1-propanone, andafter purification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (90/10), 1.28 g (80%) of theexpected product are obtained in the form of an oil.

[0205] (c)1-{5′-[3,4-Bis(benzoyloxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propan-one

[0206] In a manner similar to that of Example 1(o), by reacting 1.28 g(4.3 mmol) of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)-1-propanonewith 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, anoil is obtained, which is used without purification.

[0207] (d)1-{5′[3,4-Bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propanone

[0208] In a manner similar to that of Example 1(p), starting with1-{5′-[3,4-bis(benzoyloxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propanone,and after purification by chromatography on a column of silica elutedwith a mixture of heptane and ethyl acetate (30/70), 830 mg (43%) of theexpected product are obtained in the form of a colorless oil.

[0209] (e){4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0210] In a manner similar to that of Example 1(q), by reacting 830 mg(1.9 mmol) of1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propanonewith 5.1 ml (15.2 mmol) of ethylmagnesium bromide (3M/ether), and afterpurification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (40/60), 700 mg (77%) of{4-[6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanolare obtained in the form of white crystals with a melting point of 101°C.

EXAMPLE 4

[0211]{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0212] (a) 1-(4-Hydroxy-3-isopropylphenyl)propan-1-one

[0213] In a manner similar to that of Example 1(a), by reacting 10 g (73mmol) of 2-isopropylphenol with 6.3 ml (73 mmol) of propionyl chloride,4.5 g (32%) of the expected product are obtained in the form of whitecrystals with a melting point of 105° C.

[0214] (b) 2-Isopropyl-4-propionylphenyl 1,1,1-trifluoromethanesulfonate

[0215] In a manner similar to that of Example 1(b), by reacting 4.5 g(24 mmol) of 1-(4-hydroxy-3-isopropylphenyl)-1-propanone with 4.4 ml (26mmol) of trifluoromethanesulfonic anhydride, 7.5 g (100%) of theexpected product are obtained.

[0216] (c)1-(5′-Ethoxymethoxy-2′-ethyl-2-isopropylbiphenyl-4-yl)propan-1-one

[0217] In a manner similar to Example 1(g), by reacting 1.8 g (8 mmol)of 2-ethyl-5-ethoxymethoxyphenylboronic acid obtained in 20) with 2 g(6.2 mmol) of 2-isopropyl-4-propionylphenyl1,1,1-trifluoromethanesulfonate, a brown oil is obtained, which is usedwithout purification.

[0218] (d) 1-(2′-Ethyl-5′-hydroxy-2-isopropylbiphenyl-4-yl)propan-1-one

[0219] In a manner similar to that of Example 1(h), starting with1-(5′-ethoxymethoxy-2′-ethyl-2-isopropylbiphenyl-4-yl)propan-1-one, andafter purification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (80/20), 660 mg (35%) of theexpected product are obtained in the form of a colorless oil.

[0220] (e)1-{5′-[3,4-Bis(benzoyloxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone

[0221] In a manner similar to that of Example 1(o), by reacting 660 mg(2.2 mmol) of1-(2′-ethyl-5′-hydroxy-2-isopropylbiphenyl-4-yl)propan-1-one with 1 g(2.3 mmol) of 3,4-bis-(benzoyloxymethyl)benzyl bromide, an oil isobtained, which is used without purification.

[0222] (f)1{-5′-[3,4-Bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone

[0223] In a manner similar to that of Example 1(p), starting with1-{5′-[3,4-bis(benzoyloxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone,and after purification by chromatography on a column of silica elutedwith a mixture of heptane and ethyl acetate (50/50), 810 mg (83%) of theexpected product are obtained in the form of a colorless oil.

[0224] (g){4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol

[0225] In a manner similar to that of Example 1(q), by reacting 810 mg(1.8 mmol) of1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone with 4.8 ml (15 mmol) of ethylmagnesium bromide (3M/ether),and after purification by chromatography on a column of silica elutedwith a mixture of heptane and ethyl acetate (35/65), 600 mg (70%) of{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanolare obtained in the form of white crystals with a melting point of 109°C.

EXAMPLE 5

[0226]{2-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol

[0227] (a) (3-Bromo-4-methylphenyl)methanol

[0228] 15 g (70 mmol) of 3-bromo-4-methylbenzoic acid are placed in 150ml of anhydrous THF in a round-bottomed flask and under a stream ofnitrogen. 84 ml of 1M borane/THF are added dropwise and the reactionmedium is stirred overnight at room temperature. A THF/water (50/50)solution is added slowly at 0° C. and the mixture is then poured intosaturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic phase is dried over magnesium sulfate, filtered andthen evaporated. 14.4 g (100%) of the expected product are obtained inthe form of a yellow oil.

[0229] (b) 3-Bromo-4-methylbenzaldehyde

[0230] 14.4 g (72 mmol) of (3-bromo-4-methylphenyl)methanol are placedin 200 ml of dichloromethane in a round-bottomed flask. 62.6 g (72 mmol)of manganese oxide are added and the medium is stirred at roomtemperature overnight. The mixture is filtered through Celite and thesolvent is evaporated off. 11.8 g (85%) of the expected product areobtained in the form of an oil.

[0231] (c) 2-(3-Bromo-4-methylphenyl)[1,3]dioxolane

[0232] 11.8 g (60 mmol) of 3-bromo-4-methylbenzaldehyde are placed in150 ml of toluene in a round-bottomed flask and under nitrogen. 16.5 ml(300 mmol) of ethylene glycol and 571 mg (3 mmol) ofpara-toluenesulfonic acid are added. The mixture is refluxed for 36hours and the water formed is separated out using Dean-Stark apparatus.At room temperature, the reaction medium is poured into saturatedaqueous sodium hydrogen carbonate solution and then extracted withether. The organic phase is dried over magnesium sulfate, filtered andevaporated. 13 g (89%) of the expected product are obtained in the formof a brown oil.

[0233] (d) 5-[1,3]Dioxolan-2-yl-2-methylphenylboronic acid

[0234] In a manner similar to that of Example 2(k), by reacting 11.1 g(46 mmol) of 2-(3-bromo-4-methylphenyl)[1,3]dioxolane with 12.3 ml (55mmol) of triisopropyl borate, 6 g (88%) of product are obtained in theform of an oil.

[0235] (e) 6-Methyl-4′-propionyl-2′-propylbiphenyl-3-carbaldehyde

[0236] In a manner similar to that of Example 1(g), by reacting 2 g (6.2mmol) of 4-propionyl-2-propylphenyl 1,1,1-trifluoromethanesulfonate with1.2 g (8 mmol) of 5-[1,3]dioxolan-2-yl-2-methylphenylboronic acid, andafter purification by chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (90/10), 1.42 g (78%) of productare obtained in the form of a pale yellow oil.

[0237] (f) Dimethyl 4-bromomethylphthalate

[0238] 10 g (44.6 mmol) of dimethyl 4-hydroxymethylphthalate obtained in1(i) are placed in 75 ml of dichloromethane in a round-bottomed flaskand under a stream of nitrogen. At 5° C., a solution of 2.1 ml (22 mmol)of phosphorous tribromide is added. 2 hours later, water is addedslowly. After separation of the phases by settling, the aqueous phase isextracted with dichloromethane and the organic phases are combined,dried over magnesium sulfate, filtered and then evaporated. 8.8 g (69%)of the expected product are obtained in the form of a yellow oil.

[0239] (g) Dimethyl 4-(diethoxyphosphorylmethyl)phthalate

[0240] 65.7 g (229 mmol) of dimethyl 4-bromomethylphthalate are placedin 100 ml (583 mmol) of triethyl phosphite in a round-bottomed flask.The mixture is refluxed for 4 hours. The medium is then distilled toremove the triethyl phosphite. 60.7 g (77%) of the expected product areobtained in the form of a yellow oil.

[0241] (h) Dimethyl 4-[(Z)-2-(6-methyl-4′-propionyl-2′-propylbiphenyl-3-yl)vinyl]phthalate 2 g (6 mmol) of dimethyl4-(diethoxyphosphorylmethyl)phthalate are placed in 50 ml of THF in around-bottomed flask and under a stream of nitrogen. 3 ml of lithiumdiisopropylamide (2M/THF) are added, followed by addition of 1.42 g (5mmol) of 6-methyl-4′-propionyl-2′-propylbiphenyl-3-carbaldehyde.Stirring is continued for 3 days at room temperature. The reactionmedium is then poured into water and extracted with ethyl acetate. Theorganic phase is dried over magnesium sulfate, filtered and thenevaporated. The residue obtained is purified by chromatography on acolumn of silica eluted with a mixture of heptane and ethyl acetate(90/10). After evaporating off the solvents, 900 mg (39%) of theexpected product are obtained in the form of a yellow oil.

[0242] (i)Dimethyl4-{(Z)-2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]vinyl}-phthalate

[0243] In a manner similar to that of Example 6(c), starting with 900 mg(1.9 mmol) of dimethyl4-[(Z)-2-(6-methyl-4′-propionyl-2′-propylbiphenyl-3-yl)vinyl]phthalate,700 mg (70%) of the expected product are obtained in the form of ayellow oil.

[0244] (j) Dimethyl 4-{2-[4′(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3yl]ethyl}-phthalate

[0245] 700 mg (1.3 mmol) of dimethyl4-{(Z)-2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]vinyl}phthalateare placed in 15 ml of methanol, 15 ml of ethyl acetate and 1 ml oftriethylamine in a reactor. The reaction medium is degassed and 100 mgof palladium-on-charcoal (10%) and hydrogen to a pressure of 3.5 bar at80° C. are added. The reaction medium is filtered and evaporated to give640 mg (93%) of the expected product in the form of an oil.

[0246] (k)(4-{2-[4′(2-Ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol

[0247] 182 mg (4.8 mmol) of lithium aluminum hydride are placed in 20 mlof dry THF in a round-bottomed flask and under nitrogen. At 0° C., asolution of 640 mg (1.2 mmol) of dimethyl4-{2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}phthalatein 5 ml of THF is added dropwise. The reaction medium is stirred for 1hour at room temperature. 200 μl of water are then added very slowly,followed by addition of 200 μl of 15% sodium hydroxide solution and then600 μl of water. The medium is filtered and the filtrate is evaporatedto dryness. 640 mg (100%) of the expected product are obtained in theform of a colorless oil.

[0248] (l)1-{5′-[2-(3,4-Bis(hydroxymethyl)phenyl)ethyl]-2′-methyl-2-propylbiphenyl-4-yl}propan-1-one

[0249] 640 mg (1.4 mmol) of(4-{2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanolare placed in 15 ml of acetone and 15 ml of water in a round-bottomedflask. A spatula-tip of p-toluenesulfonic acid is added and the solutionis refluxed for 2 hours 30 minutes. At room temperature, it is pouredinto saturated aqueous sodium hydrogen carbonate solution and extractedwith ethyl acetate. The organic phase is dried over magnesium sulfate,filtered and then evaporated. The residue obtained is purified bychromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (30/70). 300 mg (50%) of the expected product areobtained in the form of a colorless oil.

[0250] (m)(4-{2-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol

[0251] In a manner similar to that of Example 1(q), by reacting 300 mg(0.7 mmol) of1-{5′-[2-(3,4-bis(hydroxymethyl)phenyl)ethyl]-2′-methyl-2-propylbiphenyl-4-yl}propan-1-onewith 1.9 ml (5.6 mmol) of ethylmagnesium bromide (3M/ether), and afterpurification on a column of silica eluted with a mixture of heptane andethyl acetate (40/60), 180 mg (56%) of(4-{2-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxy-methylphenyl)methanolare obtained in the form of white crystals with a melting point of 76°C.

EXAMPLE 6

[0252](4-{[4′-(1-Ethyl-1-hydroxypropyl)-6,2′-dimethylbiphenyl-3-ylamino]-methyl}-2-hydroxymethylphenyl)methanol

[0253] (a) 1-(4-Bromo-3-methylphenyl)propan-1-one

[0254] 24.7 g (126 mmol) of 4-bromo-3-methylbenzonitrile are dissolvedin 400 ml of anhydrous dioxane and the medium is then cooled to 0° C.124 ml (372 mmol) of ethylmagnesium bromide are added dropwise and themedium is then warmed to room temperature and stirred for 4 hours. Thereaction medium is treated with 250 ml of 3N HCl and then extracted witha water/ether mixture. A white solid is obtained after trituration fromheptane (m=14.5 g, Y=52%).

[0255] (b) 2-(4-Bromo-3-methylphenyl)-2-ethyl[1,3]dioxolane 13 g (57mmol) of 1-(4-bromo-3-methylphenyl)-1-propanone are dissolved in 130 mlof toluene. 54 ml (800 mmol) of ethylene glycol are added, followed byaddition of 1.4 g (7.4 mmol) of para-toluenesulfonic acid. The medium isequipped with a distillation assembly of Dean-Stark type and heated at125° C. for 14 hours. After treatment with dilute sodium hydroxidesolution, the organic phase is washed with water and concentrated underreduced pressure. A yellow oil is obtained (m=13.6 g, Y=88%).

[0256] (c) 2-Methyl-4-propionylbenzeneboronic acid

[0257] 1.6 g (65 mmol) of magnesium are suspended in 5 ml of THF and 0.5ml of 1,2-dibromoethane. One crystal of iodine is added. A solution of13.6 g (50 mmol) of 2-(4-bromo-3-methylphenyl)-2-ethyl[1,3]dioxolane and0.4 ml of 1,2-dibromoethane in 70 ml of THF is added slowly. The mediumis refluxed for 45 minutes after the end of the addition and then cooledto −78° C. 6.2 ml (55 mmol) of trimethyl borate are added and the mediumis maintained at this temperature for 45 minutes. 100 ml of 1N HCl arethen added and the medium is warmed to room temperature. Afterseparation of the phases by settling and concentration of the organicphase, the residue obtained is triturated from heptane: a beige-coloredsolid is obtained (m=5.1 g, Y=54%).

[0258] (d) 1-(2,2′-Dimethyl-5′-nitrobiphenyl-4-yl)propan-1-one

[0259] 2.5 g (13 mmol) of 2-methyl-4-propionylbenzeneboronic acid areplaced in 100 ml of dimethoxyethane in a round-bottomed flask, and 2.2 g(10 mmol) of 2-bromo-4-nitrotoluene and 13 ml of aqueous 2M potassiumcarbonate solution are added. The medium is degassed for 10 minutes witha flow of nitrogen, and 580 mg (0.5 mmol) oftetrakis(triphenylphosphine)palladium are then added. The medium isstirred for 14 hours at 90° C. and then worked up as usual. The residueis obtained after chromatography on a column of silica (eluent: 1 ethylacetate/9 heptane) to give 2.3 g (81%) of the expected product in theform of a yellow oil.

[0260] (e) 1-(5 ′-Amino-2,2′-dimethylbiphenyl-4-yl)propan-1-one

[0261] 2.2 g (7.8 mmol) of1-(2,2′-dimethyl-5′-nitrobiphenyl-4-yl)-1-propanone are dissolved in amixture of 80 ml of ethanol and 40 ml of water and 10 ml of acetic acid.The mixture is refluxed while 1.7 g (31 mmol) of iron powder are added.The medium is heated for 1 hour and then treated by addition of aqueousammonia, cooled and filtered through Celite. The solution obtained isdiluted in ethyl acetate and then washed with water, and the organicphase is dried and concentrated under reduced pressure. Afterchromatography on a column of silica (eluent: 60 heptane/40 ethylacetate), a yellow oil is obtained (m=1.9 g; Y=96%).

[0262] (f) Tert-butyl (6,2′-dimethyl-4′propionylbiphenyl-3-yl)carbamate

[0263] 800 mg (3.15 mmol) of1-(5′-amino-2,2′-dimethylbiphenyl-4-yl)-1-propanone are dissolved in 50ml of dichloromethane. 500 μl (3.5 mmol) of triethylamine are added,followed by addition of 760 mg (3.5 mmol) of di-tert-butyl dicarbonate.The medium is stirred at room temperature for 12 hours and then for 2hours at 50° C. The medium is treated with water and the residue is thenpurified by chromatography on a column of silica (eluent: 3 heptane/1ethyl acetate) to give a yellow crystalline solid (m.p. 119° C., m=1.05g, Y=94%).

[0264] (g)2-Benzoyloxymethyl-5-{[tert-butoxycarbonyl(6,2′-dimethyl-4′-propionylbiphenyl-3-yl)-amino]methyl}benzylbenzoate

[0265] 900 mg (2.5 mmol) oftert-butyl(6,2′-dimethyl-4′-propionylbiphenyl-3-yl)carbamate aredissolved in 30 ml of dimethylformamide. 110 mg (2.8 mmol) of 60% sodiumhydride are added and the medium is stirred for 15 minutes. 1.23 g (2.8mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide are then added and themedium is stirred for 12 hours at room temperature. After the usualwork-up, the residue obtained is purified by chromatography on a columnof silica (eluent: 8 heptane/2 ethyl acetate). A colorless oil isobtained (m=1 g, Y=55%).

[0266] (h)2-Benzoyloxymethyl-5-[(6,2′-dimethyl-4′-propionylbiphenyl-3-ylamino)methyl]benzylbenzoate

[0267] 1 g (1.4 mmol) of2-benzoyloxymethyl-5-{[tert-butoxycarbonyl(6,2′-dimethyl-4′-propionyl-biphenyl-3-yl)amino]methyl}benzylbenzoate are dissolved in 50 ml of dichloromethane. 1,1 ml (14 mmol) oftrifluoroacetic acid are added and the medium is stirred at roomtemperature for 6 hours. After extraction with water/dichloromethane,the desired product is obtained in the form of a yellowish oil (m=820mg, Y=95%).

[0268] (i)1-{5′[3,4-Bis(hydroxymethyl)benzylamino]-2,2′-dimethylbiphenyl-4-yl}-1-propanone

[0269] 800 mg (1.3 mmol) of2-benzoyloxymethyl-5-[(6,2′-dimethyl-4′-propionylbiphenyl-3-ylamino)methyl]benzylbenzoate are dissolved in methanolic 2% potassium carbonate solution andthe medium is stirred for 1 hour. After water/dichloromethaneextraction, the residue obtained is purified by chromatography on silicagel (eluent: 30 heptane/70 ethyl acetate). A yellow oil is obtained(m=470 mg, Y=88%).

[0270] (j)(4-{[4′-(1-Ethyl-1-hydroxypropyl)-6,2′-dimethylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol

[0271] 450 mg (1.1 mmol) of1-{5′-[3,4-bis(hydroxymethyl)benzylamino]-2,2′-dimethylbiphenyl-4-yl}-1-propanoneare dissolved in 30 ml of THF. 1.5 ml (4.5 mmol) of ethylmagnesiumbromide are added and the medium is stirred at room temperature for 1hour. After the usual work-up, the residue is purified by chromatographyon silica gel (eluent: 1 heptane/1 ethyl acetate). A white solid isobtained (m=130 mg; Y=27%).

[0272]¹H NMR (CDCl₃): 0.80 (t, 6H, J =7.4 Hz); 1.85 (q, 4H, J=7.5 Hz);1.91 (s, 3H); 2.06 (s, 3H); 2.86 (bs, 2H); 4.30 (s, 2H); 4.72 (s, 2H);4.73 (s, 2H); 6.45 (d, 1H, J=2.4 Hz); 6.55 (dd, 1H, J1=2.4 Hz, J2=8.1Hz); 7.04 (m, 2H); 7.15 (m, 1H); 7.24-7.37 (m, 4H).

EXAMPLE 7

[0273] Formulations

[0274] 1) Oral Route

[0275] (a) The following composition is prepared in the form of a 0.2 gtablet Compound of Example 2 0.005 g Pregelatinized starch 0.065 gMicrocrystalline cellulose 0.075 g Lactose 0.050 g Magnesium stearate0.005 g

[0276] For the treatment of ichthyosis, 1 to 3 tablets per day areadministered to an adult individual for 1 to 12 months depending on theseriousness of the case treated.

[0277] (b) A drinkable suspension intended to be packaged in 5 mlampules is prepared. Compound of Example 6 0.050 mg Glycerol 0.500 g 70%sorbitol 0.500 g Sodium saccharinate 0.010 g Methyl para-hydroxybenzoate0.040 g Flavouring q.s. Purified water q.s  5 ml

[0278] For the treatment of acne, 1 ampule per day is administered to anadult individual for 1 to 12 months depending on the seriousness of thecase treated.

[0279] (c) The following formulation intended to be packaged in gelcapsules is prepared: Compound of Example 5 0.0001 mg Corn starch 0.060g Lactose q.s. 0.300 g

[0280] The gel capsules used consist of gelatin, titanium oxide and apreserving agent. In the treatment of psoriasis, 1 gel capsule per dayis administered to an adult individual for 1 to 12 months.

[0281] (d) The following formulation intended to be packaged in gelcapsules is prepared: Compound of Example 1 0.02 mg Cyclosporin 0.050 gCorn starch 0.060 g Lactose q.s. 0.300 g

[0282] The gel capsules used consist of gelatin, titanium oxide and apreserving agent. In the treatment of psoriasis, 1 gel capsule per dayis administered to an adult individual for 1 to 12 months.

[0283] 2) Topical Route

[0284] (a) The nonionic water-in-oil cream below is prepared: Compoundof Example 5 0.100 g Mixture of emulsifying lanolin alcohols, 39.900 gwaxes and refined oils, sold by the company Beiersdorf under the name“Anhydrous eucerin” Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water q.s. 100.000 g

[0285] This cream is applied to skin afflicted with psoriasis 1 to 2times a day for 1 to 12 months.

[0286] (b) A gel is prepared by preparing the formulation below:Compound of Example 2 0.001 g Erythromycin base 4.000 gButylhydroxytoluene 0.050 g Hydroxypropylcellulose sold by the company2.000 g Hercules under the name “Klucel HF” Ethanol (at 95°) q.s 100.000g

[0287] This gel is applied to skin afflicted with dermatitis or withacne 1 to 3 times a day for 6 to 12 weeks depending on the severity ofthe case treated.

[0288] (c) An antiseborrhoeic lotion is prepared by mixing together thefollowing ingredients: Compound of Example 1 0.030 g Propylene glycol5.000 g Butylhydroxytoluene 0.100 g Ethanol (at 95°) q.s 100.000 g

[0289] This lotion is applied twice a day to a seborrhoeic scalp and asignificant improvement is observed within a period of 2 to 6 weeks.

[0290] (d) A cosmetic composition to combat the harmful effects ofsunlight is prepared by mixing together the following ingredients:Compound of Example 3 1.000 g Benzylidenecamphor 4.000 g Fatty acidtriglycerides 31.000 g Glyceryl monostearate 6.000 g Stearic acid 2.000g Cetyl alcohol 1.200 g Lanolin 4.000 g Preserving agents 0.300 gPropylene glycol 2.000 g Triethanolamine 0.500 g Fragrance 0.400 gDemineralized water q.s 100.000 g

[0291] This composition is applied daily and helps to combatphoto-induced aging.

[0292] (e) The oil-in-water cream below is prepared: Compound of Example5 0.500 g Retinoic acid 0.020 g Cetyl alcohol 4.000 g Glycerylmonostearate 2.500 g PEG-50 stearate 2.500 g Karite butter 9.200 gPropylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water q.s. 100.000 g

[0293] This cream is applied to skin afflicted with psoriasis 1 to 2times a day for 30 days for an attacking treatment, and indefinitely fora maintenance treatment.

[0294] (f) A topical gel is prepared by mixing together the followingingredients: Compound of Example 2 0.050 g Ethanol 43.000 g α-Tocopherol0.050 g Carboxyvinyl polymer sold under the 0.500 g name “Carbopol 941”by the company “Goodrich” Triethanolamine as an aqueous 3.800 g solutionat 20% by weight Water 9.300 g Propylene glycol q.s. 100.000 g

[0295] This gel is applied in the treatment of acne 1 to 3 times a dayfor 6 to 12 weeks depending on the severity of the case treated.

[0296] (g) A lotion for preventing hair loss and for promoting regrowthof the hair is prepared by mixing together the following ingredients:Compound of Example 4 0.05 g Compound sold under the name “Minoxidil”1.00 g Propylene glycol 20.00 g Ethanol 34.92 g Polyethylene glycol(molecular mass = 400) 40.00 g Butylhydroxyanisole 0.01 gButylhydroxytoluene 0.02 g Water q.s. 100.00 g

[0297] This lotion is applied 1 to 2 times a day for 3 months to a scalpwhich has suffered hair loss, and indefinitely for a maintenancetreatment.

[0298] (h) An anti-acne cream is prepared by mixing together thefollowing ingredients: Compound of Example 6 0.050 g Retinoic acid 0.010g Mixture of glyceryl stearate and polyethylene 15.000 g glycol stearate(75 mol) sold under the name “Gelot 64” by the company “Gattefosse”Polyoxyethylenated kernel oil containing 6 mol 8.000 g of ethyleneoxide, sold under the name “Labrafil M2130 CS” by the company“Gattefosse” Perhydrosqualene 10.000 g Preserving agents q.s.Polyethylene glycol (molecular mass = 400) 8.000 g Disodium salt ofethylenediamine tetraacetic acid 0.050 g Purified water q.s  100.000 g

[0299] This cream is applied to skin afflicted with dermatitis or acne 1to 3 times a day for 6 to 12 weeks.

[0300] (i) An oil-in-water cream is prepared by preparing the followingformulation: Compound of Example 2 0.020 g Betamethasone 17-valerate0.050 g S-carboxymethylcysteine 3.000 g Polyoxyethylene stearate (40 molof ethylene 4.000 g oxide) sold under the name “Myrj 52” by the company“Atlas” Sorbitan monolaurate polyoxyethylenated 1.800 g with 20 mol ofethylene oxide, sold under the name “Tween 20” by the company “Atlas”Mixture of glyceryl mono- and distearate 4.200 g sold under the name“Géléol” by the company “Gattefosse” Propylene glycol 10.000 gButylhydroxyanisole 0.010 g Butylhydroxytoluene 0.020 g Cetostearylalcohol 6.200 g Preserving agents q.s. Perhydrosqualene 18.000 g Mixtureof caprylic/capric triglycerides sold 4.000 g under the name “Miglyol812” by the company “Dynamit Nobel” Triethanolamine (99% by weight)2.500 g Water q.s. 100.000 g

[0301] This is cream is applied twice a day to skin afflicted withinflammatory dermatitis, for 30 days.

[0302] (j) The oil-in-water cream below is prepared: Lactic acid 5.000 gCompound of Example 1 0.020 g Polyoxyethylene stearate (40 mol ofethylene oxide) 4.000 g sold under the name “Myrj 52” by the company“Atlas” Sorbitan monolaurate polyoxyethylenated with 1.800 g 20 mol ofethylene oxide, sold under the name “Tween 20” by the company “Atlas”Mixture of glyceryl mono- and distearate 4.200 g sold under the name“Geleol” by the company “Gattefosse” Propylene glycol 10.000 gButylhydroxyanisole 0.010 g Butylhydroxytoluene 0.020 g Cetostearylalcohol 6.200 g Preserving agents q.s. Perhydrosqualene 18.000 g Mixtureof caprylic/capric triglycerides sold 4.000 g under the name “Miglyol812” by the company “Dynamit Nobel” Water q.s. 100.000 g

[0303] This cream is applied once a day, and helps to combat aging,whether photo-induced or chronological.

[0304] (k) The anhydrous ointment below is prepared: Compound of Example5 5.000 g Liquid petroleum jelly 50.00 g Butylhydroxytoluene 0.050 gWhite petroleum jelly q.s. 100 g

[0305] This ointment is applied twice a day for 30 days to skinafflicted with squamous dermatitis.

[0306] 3) Intralesional Route

[0307] (a) The following composition is prepared: Compound of Example 10.002 g Ethyl oleate q.s. 10 g

[0308] In the treatment of malignant melanoma, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

[0309] (b) The following composition is prepared: Compound of Example 20.050 g Olive oil q.s. 2 g

[0310] In the treatment of basocellular carcinoma, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

[0311] (c) The following composition is prepared: Compound of Example 30.1 mg Sesame oil q.s. 2 g

[0312] In the treatment of spinocellular carcinoma, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

[0313] (d) The following composition is prepared: Compound of Example 40.001 mg Methyl benzoate q.s. 10 g

[0314] In the treatment of carcinoma of the colon, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

[0315] 4) Intravenous Route

[0316] (a) The injectable lipid emulsion below is prepared: Compound ofExample 5 0.001 mg Soyabean oil 10.000 g Egg phospholipid 1.200 gGlycerol 2.500 g Water for injection q.s 100.000 g

[0317] In the treatment of psoriasis, the composition is injected intoan adult individual at a frequency of 1 to 7 times a week for 1 to 12months.

[0318] (b) The injectable lipid emulsion below is prepared: Compound ofExample 6 0.010 g Cotton oil 10.000 g Soyabean lecithin 0.750 g Sorbitol5.000 g DL, α-tocopherol 0.100 g Water for injection q.s 100.000 g

[0319] In the treatment of ichthyosis, the composition is injected intoan adult individual at a frequency of 1 to 7 times a week for 1 to 12months.

[0320] (c) The injectable lipid emulsion below is prepared: Compound ofExample 1 0.001 g Soyabean oil 15.000 g Acetylated monoglycerides 10.000g Pluronic F-108 1.000 g Glycerol 2.500 g Water for injection q.s100.000 g

[0321] In the treatment of leukaemia, the composition is injected intoan adult individual at a frequency of 1 to 7 times a week for 1 to 12months.

[0322] (d) The mixed micellar composition below is prepared: Compound ofExample 2 0.001 g Lecithin 16.930 g Glycocholic acid 8.850 g Water forinjection q.s 100.000 g

[0323] In the treatment of malignant melanoma, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

[0324] (e) The cyclodextrin composition below is prepared: Compound ofExample 5 0.1 mg β-Cyclodextrin 0.100 g Water for injection q.s 10.000 g

[0325] In the treatment of graft rejection, the composition is injectedinto an adult individual at a frequency of 1 to 7 times a week for 1 to12 months.

[0326] (f) The cyclodextrin composition below is prepared: Compound ofExample 3 0.010 g 2-Hydroxypropyl-β-cyclodextrin 0.100 g Water forinjection q.s 10.000 g

[0327] In the treatment of cancer of the kidney, the composition isinjected into an adult individual at a frequency of 1 to 7 times a weekfor 1 to 12 months.

EXAMPLE 8

[0328] Tests to Evaluate the Biological Activity of the Compounds of theInvention—Activity on the Differentiation of HL60 Cells

[0329] Calcitrol induces the differentiation of promyelocytic leukaemiacells (HL60) into monocytes/macrophages. This differentiation-inductiveeffect is a well-characterized marker of cellular vitamin D. One of themost important antimicrobial products of macrophages is hydrogenperoxide, which may be analysed experimentally by the reduction of NBT(Nitroblue Tetrazolium).

[0330] The method used is as follows: the HL60 cells are inoculated into6-well plates and then treated immediately with a test compound. Afterculturing for 4 days, the cells are incubated with phorbol TPA ester andNBT for a short period and the differentiated cells, i.e., the ones thatare positive to NBT, are counted.

[0331] The differentiation-inductive effect on HL60 cells of thecompounds according to the invention and also that of the referencecompound, calcitriol, are given in Table I. The results show that thecompounds of Examples 1 to 4 have differentiation-inducing activity onHL60 cells similar to that of calcitriol, the compound of Example 5 evenhaving markedly superior activity.

[0332] As regards the compound of Example 6, it shows less good activitycompared with calcitriol, but nevertheless remains a very advantageouscompound when compared with the compounds of the prior art. TABLE I TESTCOMPOUND AC50-HL60 (in nM) Calcitriol 10.7 Compound of Example 1 7.6Compound of Example 2 15.0 Compound of Example 3 11.0 Compound ofExample 4 27.0 Compound of Example 5 1.8 Compound of Example 6 147

EXAMPLE 9

[0333] Tests to Evaluate the Biological Activity of the Compounds of theInvention—Measurement of the VDR Agonist Activity (AC50 hVDR)

[0334] The VDR agonist activity of the compounds of the invention may betested on the HeLa cell line by cotransfection of the expression vectorof the human VDR receptor and of the reporter plasmid p240Hase-CAT whichcontains the region −1399 to +76 of rat 24-hydroxylase promoter, clonedupstream of the coding phase of the chloramphenicol-acetyltransferase(CAT) gene. 18 hours after cotransfection, the test compound is added tothe medium. After treatment for 18 hours, the CAT activity of the celllysates is assayed by means of an ELISA test (Enzyme LinkedImmunoSorbent Assay, sold by Roche Molecular Biochemicals). The agonistactivity may be characterized in this system of cotransfection bydetermining the dose required to achieve 50% of the maximum activity ofthe test compound (AC50).

[0335] The measurement of the VDR agonist activity of the compoundsaccording to the invention and also that of the reference compound,calcitriol, are given in Table II.

[0336] These results show that the compounds according to the presentinvention have activities that are comparable to that of calcitriol, thecompound of Example 5 having, in this case also, superior activity.

[0337] These results once again show that the compound of Example 6shows less good activity compared with calcitriol, but neverthelessremains a very advantageous compound when compared with the compounds ofthe prior art. TABLE II TEST COMPOUND AC50-hVDR (in nM) Calcitriol 2.5Compound of Example 1 2.4 Compound of Example 2 4.1 Compound of Example3 2.2 Compound of Example 4 3.2 Compound of Example 5 0.6 Compound ofExample 6 50

EXAMPLE 10

[0338] Tests to Evaluate the Biological Activity of the Compounds of theInvention—Activity on the Proliferation of Human Keratinocytes

[0339] It is known that 1,25-dihydroxyvitamin D3, known as calcitrioland corresponding to natural vitamin D, inhibits the proliferation ofhuman keratinocytes in culture.

[0340] The method used is as follows: normal human keratinocytes areinoculated at low density into a 24-well plate. After 4 hours, the testcompounds are added to the culture medium. After culturing for 5 days,the proliferation of the keratinocytes is determined by incorporating5-bromo-2′-deoxyuridine (BrdU) into the DNA. The amount of BrdUincorporated is then measured using the ELISA test (Enzyme LinkedImmunoSorbent Assay, sold by Roche Molecular Biochemicals).

[0341] The inhibitory effect on keratinocyte proliferation of thecompounds according to the invention and of calcitriol used as referencecompound is summarized in Table III. The IC50 value indicates theconcentration of the test compound for which the compound inhibits theproliferation of the keratinocytes by 50%.

[0342] These results make it possible to show that the compounds of theinvention have inhibitory activity on keratinocyte proliferation in thesame ranges of values as calcitriol; the compound of Example 5 isdistinguished by an activity more than 5 times greater than that ofcalcitriol.

[0343] As regards the compound of Example 6, it shows less good activitycompared with calcitriol, but nevertheless remains a very advantageouscompound when compared with the compounds of the prior art. TABLE IIIMEASURED ACTIVITY IC50-proliferation of KHNs (in nM) Calcitriol 15.3Compound of Example 1 16.0 Compound of Example 2 53.0 Compound ofExample 3 15.0 Compound of Example 4 26.0 Compound of Example 5 2.4Compound of Example 6 122

[0344] While the invention has been described in terms of variousspecific and preferred embodiments, the skilled artisan will appreciatethat various modifications, substitutions, omissions, and changes may bemade without departing from the spirit thereof. Accordingly, it isintended that the scope of the present invention be limited solely bythe scope of the following claims, including equivalents thereof.

What is claimed is:
 1. A triaromatic vitamin D analogue having thestructural formula (I) below:

in which: —X—Y represents the following structural bonds:—CH₂—CH₂——CH₂—O——O—CH₂——CH₂—N(R₄)— R₄ having the meanings given below,R₁ represents a methyl radical or an ethyl radical, R₂ represents anethyl radical, a propyl radical or an isopropyl radical, R₃ representsan ethyl radical or a trifluoromethyl radical, R₄ represents a hydrogenatom, a methyl radical, an ethyl radical or a propyl radical, and theoptical and geometrical isomers of the said compounds of formula (I),and also the salts thereof.
 2. The vitamin D analogue as defined byclaim 1, in the form of a salt of a mineral or organic acid,hydrochloric acid, sulfuric acid, acetic acid, fumaric acid,hemisuccinic acid, maleic acid or mandelic acid.
 3. The vitamin Danalogue as defined by claim 1, selected from the group consisting of:1-{5-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;2-{5-[6,2′-Diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol;3-{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;4-{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;5-(4-{2-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol;6-{4-[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-ylmethoxy]-2-hydroxymethylphenyl}methanol;7-(4-{[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;8-[4-({[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;9-[4-({Ethyl-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;10-[4-({[4′-(1-Ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]propylamino}methyl)-2-hydroxymethylphenyl]methanol;11-(2-Hydroxymethyl-4-{2-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1trifluoromethyl-ethyl)biphenyl-3-yl]ethyl}phenyl)methanol;12-{2-Hydroxymethyl-4-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yloxymethyl]phenyl}methanol;13-{2-Hydroxymethyl-4-[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylmethoxy]phenyl}methanol;14-(2-Hydroxymethyl-4-{[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylamino]methyl}phenyl)methanol;15-[2-Hydroxymethyl-4-({N-methyl[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)phenyl]methanol;16-[4-({N-Ethyl[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;17-[2-Hydroxymethyl-4-({[6-methyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]N-propyl-amino}methyl)phenyl]methanol;18-(4-{2-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxy-methylphenyl)methanol;19-{4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ylmethoxy]-2-hydroxy-methylphenyl}methanol;20-(4-{[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;21-[4-({[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;22-[4-({Ethyl-[6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;23-[4-({[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yl]propylamino}methyl)-2-hydroxymethylphenyl]methanol;24-(4-{2-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol;25-{4-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol;26-{4-[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylmethoxy]-2-hydroxymethylphenyl}methanol;27-(4-{[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol;28-[4-({[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]methanol;29-[4-({N-Ethyl[6-ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]amino}methyl)-2-hydroxymethylphenyl]methanol;30-[4-({[6-Ethyl-2′-propyl-4′-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)biphenyl-3-yl]-N-propyl-amino}methyl)-2-hydroxymethylphenyl]methanol;31-(4-{[4′-(1-Ethyl-1-hydroxypropyl)-6,2′-dimethylbiphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)methanol,and mixtures thereof.
 4. The vitamin D analogue as defined by claim 1,wherein formula (I): (i) —X—Y— represents —CH₂—CH₂—; (ii) R₁ is an ethylradical; (iii) R₂ is a propyl radical; (iv) R₃ is an ethyl radical. 5.The vitamin D analogue as defined by claim 1, wherein formula (I): (i)—X—Y— represents —CH₂—CH₂—; (ii) R₁ is an ethyl radical; (iii) R₂ is apropyl radical; (iv) R₃ is an ethyl radical.
 6. A regime or regimen fortreating:
 1. dermatological complaints associated with a differentiationor proliferation disorder of keratinocytes or sebocytes; 2.keratinization disorders;
 3. dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent;
 4. inflammatory complaints not showing a keratinizationdisorder;
 5. dermal or epidermal proliferations;
 6. dermatologicaldisorders such as bullous dermatoses and collagen diseases;
 7. aging ofthe skin, whether photo-induced or chronological aging, or for reducingactinic keratoses and pigmentations, or any cutaneous pathologiesassociated with chronological or actinic aging;
 8. cicatrizationdisorders and stretch marks;
 9. sebaceous function disorders such asacneic hyperseborrhoea or simple seborrhoea or alternatively seborrhoeiceczema; or
 10. dermatological complaints with an immunologicalcomponent, comprising administering to an individual subject in need ofsuch treatment, for such period of time as required to elicit thedesired therapeutic effect, a thus-effective amount of a vitamin Danalogue as defined in claim
 1. 7. The regime or regimen as defined byclaim 6, comprising treating the dermatological complaints associatedwith a differentiation or proliferation disorder of keratinocytes orsebocytes relate to common acne, comedones, polymorphonuclearleukocytes, acne rosacea, nodulocystic acne, acne conglobata, senileacne and secondary acnes, solar acne, acne medicamentosa or occupationalacne.
 8. The regime or regimen as defined by claim 6, comprisingtreating the keratinization disorders related to ichthyosis,ichthyosiform states, Darier's disease, palmoplantar keratoderma,leukoplakia and leukoplakiform conditions, or cutaneous or mucous(buccal) lichen.
 9. The regime or regimen as defined by claim 6,comprising treating the dermatological complaints associated with akeratinization disorder with an inflammatory and/or immunoallergiccomponent concern, all forms of psoriasis, whether cutaneous, mucous orungual psoriasis, psoriatic rheumatism, and cutaneous atopy, eczema orrespiratory atopy or gingival hypertrophy.
 10. The regime or regimen asdefined by claim 6, comprising treating the dermal or epidermalproliferations, benign or malignant, of non-viral origin or of viralorigin, common warts, flat warts and verruciform epidermodysplasia, andoral or florid papillomatoses, and proliferations induced by ultravioletradiation, and basocellular or spinocellular epithelioma.
 11. Apharmaceutical composition comprising at least on vitamin D analogue asdefined by claim 1, formulated into a therapeutically acceptablevehicle, diluent or carrier therefor.
 12. The pharmaceutical compositionaccording to claim 11, comprising from 0.001% to 5% by weight of said atleast one vitamin D analogue.
 13. A cosmetic composition comprising atleast one vitamin D analogue as defined by claim 1, formulated into acosmetically acceptable vehicle, diluent or carrier therefor.
 14. Thecosmetic composition according to claim 13, comprising from 0.001% to 3%by weight of said at least one vitamin D analogue.
 15. A regime orregimen for preventing and/or treating photo-induced or chronologicalaging of the skin, comprising administering to an individual subject inneed of such treatment, for such period of time as required to elicitthe desired therapeutic effect, a thus-effective amount of the cosmeticcomposition as defined by claim 13.